Drug delivery systems

ABSTRACT

Matrix controlled diffusion drug delivery systems based on one or more silicone-containing monomers of the general formula:  
                 
 
wherein x, y, m, m′, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Z and Z′ are as defined herein are provided, wherein the matrix controlled diffusion drug delivery systems are sized and configured for back of the eye delivery.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates generally to hydrogels, drug deliverysystems, and methods of treatment.

2. Description of Related Art

Conventional drug delivery involving frequent periodic dosing is notideal or practical in many instances. For example, with more toxicdrugs, conventional periodic dosing can result in high initial druglevels at the time of dosing, followed by low drug levels between dosesoften times below levels of therapeutic value. Likewise, conventionalperiodic dosing may not be practical or therapeutically effective incertain instances such as with pharmaceutical therapies targeting areasof the inner eye or brain in need of treatment such as the retina.

During the last two decades, significant advances have been made in thedesign of controlled release drug delivery systems. See, e.g., U.S.Patent Application Publication Nos. 2004/0043067 and 2004/0253293. Suchadvances have been made in an attempt to overcome some of the drugdelivery shortcomings noted above. In general, controlled release drugdelivery systems include both sustained drug delivery systems designedto deliver a drug for a predetermined period of time, and targeted drugdelivery systems designed to deliver a drug to a specific area or organof the body. Sustained and/or targeted controlled release drug deliverysystems may vary considerably by mode of drug release within three basicdrug controlled release categories. Basic drug controlled releasecategories include diffusion controlled release, chemical erosioncontrolled release and solvent activation controlled release. In adiffusion controlled release drug delivery system, a drug is surroundedby an inert barrier and diffuses from an inner reservoir, or a drug isdispersed throughout a polymer and diffuses from the polymer matrix. Ina chemical erosion controlled release drug delivery system, a drug isuniformly distributed throughout a biodegradable polymer. Thebiodegradable polymer is designed to degrade as a result of hydrolysisto then uniformly release the drug. In a solvent activation controlledrelease drug delivery system, a drug is immobilized on polymers within adrug delivery system. Upon solvent activation, the solvent sensitivepolymer degrades or swells to release the drug. Unfortunately,controlled release drug delivery systems to date do not provide a meansby which one may manipulate and control drug delivery systems' drugrelease rate for specific drugs over a broad range of drugs.

Because of the noted shortcomings of current controlled release drugdelivery systems, a need exists for controlled release drug deliverysystems that allow for manipulation and control of drug release ratesdepending on the drug to be delivered, the location of delivery, thepurpose of delivery and/or the therapeutic requirements of theindividual patient.

SUMMARY OF THE INVENTION

In accordance with one embodiment of the present invention, a matrixcontrolled diffusion drug delivery system comprising a therapeuticallyeffective amount of one or more pharmaceutically active agents entrappedin a polymerization product of a monomeric mixture comprising one ormore silicone-containing monomers of the general formula:

wherein x, y, m, m′, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, Z and Z′ are asdefined herein, wherein the matrix controlled diffusion drug deliverysystem is sized and configured for back of the eye delivery.

In accordance with a second embodiment of the present invention, aprocess for preparing a matrix controlled diffusion drug delivery systemsized and configured for back of the eye delivery is provided, theprocess comprising entrapping a therapeutically effective amount of oneor more pharmaceutically active agents in a polymerization product of amonomeric mixture comprising one or more silicone-containing monomers ofthe general formula:

wherein x, y, m, m′, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, Z and Z′ are asdefined herein.

In accordance with a third embodiment of the present invention, aprocess for preparing a matrix controlled diffusion drug delivery systemsized and configured for back of the eye delivery is provided, theprocess comprising (a) swelling a polymerization product of a monomericmixture comprising one or more silicone-containing monomers of thegeneral formula:

wherein x, y, m, m′, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, Z and Z′ are asdefined herein, in a swelling solution comprising one or more solventsand a therapeutically effective amount of one or more pharmaceuticallyactive agents; and (b) removing the polymerization product from thesolution to provide the matrix controlled diffusion drug delivery systemcomprising the therapeutically effective amount of one or morepharmaceutically active agents entrapped in the polymerization product.

In accordance with a fourth embodiment of the present invention, aprocess for preparing a matrix controlled diffusion drug delivery systemsized and configured for back of the eye delivery is provided, theprocess comprising polymerizing a monomeric mixture comprising one ormore silicone-containing monomers of the general formula:

wherein x, y, m, m′, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, Z and Z′ are asdefined herein, in the presence of a therapeutically effective amount ofone or more pharmaceutically active agents to provide the matrixcontrolled diffusion drug delivery system comprising the therapeuticallyeffective amount of one or more pharmaceutically active agents entrappedin the polymerization product.

In accordance with a fifth embodiment of the present invention, a methodof treating an ophthalmic state, disease, disorder, injury or conditionis provided, the method comprising administering to a mammal in need ofsuch treatment a matrix controlled diffusion drug delivery systemcomprising a therapeutically effective amount of one or morepharmaceutically active agents entrapped in a polymerization product ofa monomeric mixture comprising one or more silicone-containing monomersof the general formula:

wherein x, y, m, m′, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, Z and Z′ are asdefined herein, wherein the matrix controlled diffusion drug deliverysystem is sized and configured for back of the eye delivery.

The drug delivery systems of the present invention may advantageously bedesigned to allow for manipulation and control of drug release rates,which may be based on the drug to be delivered, the location ofdelivery, the purpose of delivery and/or the therapeutic requirements ofthe individual patient such that treatment of a disease, disorder orinjury in a mammal may be achieved. The matrix controlled diffusion drugdelivery system are also advantageously sized and configured for back ofthe eye delivery of the one or more pharmaceutically active agents.

The term “monomer” and like terms as used herein denote relatively lowmolecular weight compounds that are polymerizable by, for example, freeradical polymerization, as well as higher molecular weight compoundsalso referred to as “prepolymers”, “macromonomers”, and related terms.Accordingly, it is to be understood that the term “silicon-containingmonomer(s) include corresponding prepolymers.

The term “(meth)” as used herein denotes an optional methyl substituent.Accordingly, terms such as “(meth)acrylate” denotes either methacrylateor acrylate, and “(meth)acrylic acid” denotes either methacrylic acid oracrylic acid.

The term “treating” or “treatment” of a state, disease, disorder, injuryor condition as used herein shall be understood to mean (1) preventingor delaying the appearance of clinical symptoms of the state, disease,disorder, injury or condition developing in a mammal that may beafflicted with or predisposed to the state, disease, disorder, injury orcondition but does not yet experience or display clinical or subclinicalsymptoms of the state, disease, disorder, injury or condition, (2)inhibiting the state, disease, disorder, injury or condition, i.e.,arresting or reducing the development of the disease or at least oneclinical or subclinical symptom thereof, or (3) relieving the state,disease, disorder, injury or condition, i.e., causing regression of thestate, disease, disorder, injury or condition or at least one of itsclinical or subclinical symptoms.

The term “delivering” as used herein shall be understood to meanproviding a therapeutically effective amount of a pharmaceuticallyactive agent to a particular location within a host causing atherapeutically effective concentration of the pharmaceutically activeagent at the particular location.

The term “subject” or “patient” or “host” or “mammal” as used hereinrefers to mammalian animals and humans.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation depicting the percent cumulativedrug release rate over time for a M₂D₂ (200A) siloxane loaded with 30%w/w fluocinolone acetonide.

FIG. 2 is a graphical representation depicting the percent cumulativedrug release rate over time for a M₂D₅₀ (195A) siloxane loaded with 30%w/w fluocinolone acetonide.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to matrix controlled diffusion drugdelivery systems based on one or more silicone-containing monomers andare sized and configured for back of the eye drug delivery for thetreatment of a state, disease, disorder, injury or condition in a mammalin need of treatment such as an ophthalmic disease in a mammal. Thesubject matrix controlled diffusion drug delivery systems advantageouslyallow for manipulation and control of drug release rates which may bebased on, for example, the drug to be delivered, the location ofdelivery, the purpose of delivery and/or the therapeutic requirements ofthe individual patient. The rate of release of the pharmaceuticallyactive agents can be controlled by manipulating thehydrophobic/hydrophilic balance of the silicone-containing monomer(s) toachieve the desired rate of drug release.

The monomeric mixtures for use in forming the matrix controlleddiffusion drug delivery systems of the present invention will include atleast one or more silicone-containing monomers represented by thegeneral formula I:

wherein x and y are independently integers from 0 to about 300; m and m′are independently integers from 1 to about 6, R is independently astraight or branched, substituted or unsubstituted, C₁-C₃₀ alkyl group,a C₁-C₃₀ fluoroalkyl group, an alkyl ether, cycloalkyl ether,cycloalkylalkyl ether, cycloalkenyl ether, aryl ether, arylalkyl etheror a polyether containing group or a C₁-C₃₀ alkylamide group, R¹, R²,R³, R⁴, R⁵, R⁶ and R⁷ are independently hydrogen, a straight or branchedC₁-C₃₀ alkyl group, a C₁-C₃₀ fluoroalkyl group, a C₁-C₂₀ ester group, analkyl ether, cycloalkyl ether, cycloalkylalkyl ether, cycloalkenylether, aryl ether, arylalkyl ether or polyether containing group, anureido group, an amide group, an amine group, a substituted orunsubstituted C₁-C₃₀ alkoxy group, a substituted or unsubstituted C₃-C₃₀cycloalkyl group, a substituted or unsubstituted C₃-C₃₀ cycloalkylalkylgroup, a substituted or unsubstituted C₃-C₃₀ cycloalkenyl group, asubstituted or unsubstituted C₅-C₃₀ aryl group, a substituted orunsubstituted C₅-C₃₀ arylalkyl group, a substituted or unsubstitutedC₅-C₃₀ heteroaryl group, a substituted or unsubstituted C₃-C₃₀heterocyclic ring, a substituted or unsubstituted C₄-C₃₀heterocyclolalkyl group, a substituted or unsubstituted C₆-C₃₀heteroarylalkyl group, fluorine, a vinyl group, a C₅-C₃₀ fluoroarylgroup, or a hydroxyl group; X is independently a bond, a straight orbranched C₁-C₃₀ alkyl group, a C₁-C₃₀ fluoroalkyl group, a substitutedor unsubstituted C₅-C₃₀ arylalkyl group, a substituted or unsubstitutedC₁-C₃₀ alkoxy group, an ether, polyether, sulfide, or amino-containinggroup and Z and Z′ are independently a polymerizable ethylenicallyunsaturated organic radical.

Representative examples of alkyl groups for use herein include, by wayof example, a straight or branched hydrocarbon chain radical containingcarbon and hydrogen atoms of from 1 to about 18 carbon atoms with orwithout unsaturation, to the rest of the molecule, e.g., methyl, ethyl,n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, etc., and thelike.

Representative examples of fluoroalkyl groups for use herein include, byway of example, a straight or branched alkyl group as defined abovehaving one or more fluorine atoms attached to the carbon atom, e.g.,—CF₃, —CF₂CF₃, —CH₂CF₃, —CH₂CF₂H, —CF₂H and the like.

Representative examples of ester groups for use herein include, by wayof example, a carboxylic acid ester having one to 20 carbon atoms andthe like.

Representative examples of ether or polyether containing groups for useherein include, by way of example, an alkyl ether, cycloalkyl ether,cycloalkylalkyl ether, cycloalkenyl ether, aryl ether, arylalkyl etherwherein the alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, andarylalkyl groups are defined above, e.g., alkylene oxides, poly(alkyleneoxide)s such as ethylene oxide, propylene oxide, butylene oxide,poly(ethylene oxide)s, poly(ethylene glycol)s, poly(propylene oxide)s,poly(butylene oxide)s and mixtures or copolymers thereof, an ether orpolyether group of the general formula —R⁸OR⁹, wherein R⁸ is a bond, analkyl, cycloalkyl or aryl group as defined above and R⁹ is an alkyl,cycloalkyl or aryl group as defined above, e.g., —CH₂CH₂OC₆H₅ and—CH₂CH₂OC₂H₅, and the like.

Representative examples of amide groups for use herein include, by wayof example, an amide of the general formula —R¹⁰C(O)NR¹¹R¹² wherein R¹⁰,R¹¹ and R¹² are independently C₁-C₃₀ hydrocarbons, e.g., R¹⁰ can bealkylene groups, arylene groups, cycloalkylene groups and R¹¹ and R¹²can be alkyl groups, aryl groups, and cycloalkyl groups as definedherein and the like.

Representative examples of amine groups for use herein include, by wayof example, an amine of the general formula —R¹³N R¹⁴R¹⁵ wherein R¹³ isa C₂-C₃₀ alkylene, arylene, or cycloalkylene and R¹⁴ and R¹⁵ areindependently C₁-C₃₀ hydrocarbons such as, for example, alkyl groups,aryl groups, or cycloalkyl groups as defined herein, or a quaternaryammonium compound of the general formula

wherein R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are independently C₁-C₃₀ hydrocarbons suchas, for example, alkyl groups, aryl groups, or cycloalkyl groups asdefined herein and M is an anion, and the like.

Representative examples of an ureido group for use herein include, byway of example, an ureido group having one or more substituents orunsubstituted ureido. The ureido group preferably is an ureido grouphaving 1 to 12 carbon atoms. Examples of the substituents include alkylgroups and aryl groups. Examples of the ureido group include3-methylureido, 3,3-dimethylureido, and 3-phenylureido.

Representative examples of alkoxy groups for use herein include, by wayof example, an alkyl group as defined above attached via oxygen linkageto the rest of the molecule, i.e., of the general formula —OR²⁰, whereinR²⁰ is an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl or anarylalkyl as defined above, e.g., —OCH₃, —OC₂H₅, or —OC₆H₅, and thelike.

Representative examples of cycloalkyl groups for use herein include, byway of example, a substituted or unsubstituted non-aromatic mono ormulticyclic ring system of about 3 to about 18 carbon atoms such as, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,perhydronapththyl, adamantyl and norbornyl groups bridged cyclic groupor sprirobicyclic groups, e.g., sprio-(4,4)-non-2-yl and the like,optionally containing one or more heteroatoms, e.g., O and N, and thelike.

Representative examples of cycloalkylalkyl groups for use hereininclude, by way of example, a substituted or unsubstituted cyclicring-containing radical containing from about 3 to about 18 carbon atomsdirectly attached to the alkyl group which are then attached to the mainstructure of the monomer at any carbon from the alkyl group that resultsin the creation of a stable structure such as, for example,cyclopropylmethyl, cyclobutylethyl, cyclopentylethyl and the like,wherein the cyclic ring can optionally contain one or more heteroatoms,e.g., O and N, and the like.

Representative examples of cycloalkenyl groups for use herein include,by way of example, a substituted or unsubstituted cyclic ring-containingradical containing from about 3 to about 18 carbon atoms with at leastone carbon-carbon double bond such as, for example, cyclopropenyl,cyclobutenyl, cyclopentenyl and the like, wherein the cyclic ring canoptionally contain one or more heteroatoms, e.g., O and N, and the like.

Representative examples of aryl groups for use herein include, by way ofexample, a substituted or unsubstituted monoaromatic or polyaromaticradical containing from about 5 to about 25 carbon atoms such as, forexample, phenyl, naphthyl, tetrahydronapthyl, indenyl, biphenyl and thelike, optionally containing one or more heteroatoms, e.g., O and N, andthe like.

Representative examples of arylalkyl groups for use herein include, byway of example, a substituted or unsubstituted aryl group as definedabove directly bonded to an alkyl group as defined above, e.g.,—CH₂C₆H₅, —C₂H₅C₆H₅ and the like, wherein the aryl group can optionallycontain one or more heteroatoms, e.g., O and N, and the like.

Representative examples of fluoroaryl groups for use herein include, byway of example, an aryl group as defined above having one or morefluorine atoms attached to the aryl group.

Representative examples of heterocyclic ring groups for use hereininclude, by way of example, a substituted or unsubstituted stable 3 toabout 15 membered ring radical, containing carbon atoms and from one tofive heteroatoms, e.g., nitrogen, phosphorus, oxygen, sulfur andmixtures thereof. Suitable heterocyclic ring radicals for use herein maybe a monocyclic, bicyclic or tricyclic ring system, which may includefused, bridged or spiro ring systems, and the nitrogen, phosphorus,carbon, oxygen or sulfur atoms in the heterocyclic ring radical may beoptionally oxidized to various oxidation states. In addition, thenitrogen atom may be optionally quatemized; and the ring radical may bepartially or fully saturated (i.e., heteroaromatic or heteroarylaromatic). Examples of such heterocyclic ring radicals include, but arenot limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl,tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl,oxazolyl, oxazolinyl, oxasolidinyl, triazolyl, indanyl, isoxazolyl,isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl,isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl,indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl,quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl,thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl,tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinyl sulfone,dioxaphospholanyl, oxadiazolyl , chromanyl, isochromanyl and the likeand mixtures thereof.

Representative examples of heteroaryl groups for use herein include, byway of example, a substituted or unsubstituted heterocyclic ring radicalas defined above. The heteroaryl ring radical may be attached to themain structure at any heteroatom or carbon atom that results in thecreation of a stable structure.

Representative examples of heteroarylalkyl groups for use hereininclude, by way of example, a substituted or unsubstituted heteroarylring radical as defined above directly bonded to an alkyl group asdefined above. The heteroarylalkyl radical may be attached to the mainstructure at any carbon atom from the alkyl group that results in thecreation of a stable structure.

Representative examples of heterocyclo groups for use herein include, byway of example, a substituted or unsubstituted heterocylic ring radicalas defined above. The heterocyclo ring radical may be attached to themain structure at any heteroatom or carbon atom that results in thecreation of a stable structure.

Representative examples of heterocycloalkyl groups for use hereininclude, by way of example, a substituted or unsubstituted heterocylicring radical as defined above directly bonded to an alkyl group asdefined above. The heterocycloalkyl radical may be attached to the mainstructure at carbon atom in the alkyl group that results in the creationof a stable structure.

Representative examples of a “polymerizable ethylenically unsaturatedorganic radicals” include, by way of example, (meth)acrylate-containingradicals, (meth)acrylamide-containing radicals,vinylcarbonate-containing radicals, vinylcarbamate-containing radicals,styrene-containing radicals and the like or a polymerizableethylenically unsaturated organic radical represented by the generalformula:

wherein R²¹ is hydrogen or methyl; R²² is independently hydrogen, analkyl radical having 1 to 6 carbon atoms, or a —CO—Y—R²⁴ radical whereinY is —O—, —S—or —NH—; R²⁴ is a divalent alkylene radical having 1 toabout 10 carbon atoms; R²³ is an alkyl radical having 1 to about 12carbon atoms; B denotes —CO—or —OCO—; A denotes —O—or —NH—; Ar denotesan aromatic radical having 6 to about 30 carbon atoms; w is 0 to 6; a is0 or 1; b is 0 or 1; and c is 0 or 1.

The substituents in the ‘substituted alkyl’, ‘substituted alkoxy’,‘substituted cycloalkyl’, ‘substituted cycloalkylalkyl’, ‘substitutedcycloalkenyl’, ‘substituted arylalkyl’, ‘substituted aryl’, ‘substitutedheterocyclic ring’, ‘substituted heteroaryl ring,’‘substitutedheteroarylalkyl’, ‘substituted heterocycloalkyl ring’, ‘substitutedcyclic ring’ and ‘substituted carboxylic acid derivative’ may be thesame or different with one or more selected from the group such ashydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio(═S),substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted amino,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted heterocycloalkyl ring, substituted orunsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclicring, substituted or unsubstituted guanidine, —COOR_(x), —C(O)R_(x),—C(S)R_(x), —C(O)NR_(x)R_(y), —C(O)ONR_(x)R_(y), —NR_(x)CONR_(y)R_(z),—N(R_(x))SOR_(y), —N(R_(x))SO₂R_(y), —(═N—N(Rx)R_(y)),—NR_(x)C(O)OR_(y), —NR_(x)R_(y), —NR_(x)C(O)R_(y)—,—NR_(x)C(S)R_(y)—NR_(x)C(S)NR_(y)R_(z), —SONR_(x)R_(y)—,—SO₂NR_(x)R_(y)—, —OR_(x), —OR_(x)C(O)NR_(y)R_(z), —OR_(x)C(O)OR_(y)—,—OC(O)R_(x), —OC(O)NR_(x)R_(y), —R_(x)NR_(y)C(O)R_(z), —R_(x)OR_(y),—R_(x)C(O)OR_(y), —R_(x)C(O)NR_(y)R_(z), —R_(x)C(O)R_(x),—R_(x)OC(O)R_(y), —SR_(x), —SOR_(x), —SO₂R_(x), —ONO₂, wherein R_(x),R_(y) and R_(z) in each of the above groups can be the same or differentand can be a hydrogen atom, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted amino, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, ‘substituted heterocycloalkylring’ substituted or unsubstituted heteroarylalkyl, or a substituted orunsubstituted heterocyclic ring.

In one embodiment, in the silicone-containing monomer x is from 1 toabout 300 and preferably from about 20 to about 200, y is from 1 toabout 300 and preferably from about 20 to about 200, each R isindependently a straight or branched C₁-C₃₀ alkyl group, a straight orbranched C₁-C₃₀ fluoroalkyl group, an alkyl ether or polyethercontaining group and a straight or branched C₁-C₃₀ alkylamide group, R¹,R², R³, R⁴, R⁵, R⁶ and R⁷ are independently a straight or branched,saturated or unsaturated C₁-C₃₀ alkyl group and preferably a C₁-C₆ alkylgroup, X is independently one or more C₁-C₃₀ alkyl ether groups and Zand Z′ are (meth)acrylate-containing radicals. In one embodiment, asilicon-containing monomer(s) is represented by the general formula II:

wherein x, y, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and X have the aforestatedmeanings and R²⁵ is independently hydrogen or methyl.

Applicable silicon-containing monomers of formulae I and II employed inthe monomeric mixtures for use in the drug delivery systems of thepresent invention are well known in the art and may be synthesized byknown techniques and does not constitute a part of the presentinvention. Numerous examples of such silicon-containing monomers areprovided in, e.g., U.S. Pat. No. 4,153,641 (Deichert et al.), U.S. Pat.No. 5,260,000 (Nandu et al.); U.S. Pat. No. 5,310,779 (Lai); U.S. Pat.No. 5,387,662 (Kunzler et al.); U.S. Pat. No. 5,449,729 (Lai); U.S. Pat.No. 5,512,205 (Lai); U.S. Pat. No. 5,610,252 (Bambury et al.); U.S. Pat.No. 5,616,757 (Bambury et al.); U.S. Pat. No. 5,710,302 (Kunzler etal.); U.S. Pat. No. 5,714,557 (Kunzler et al.); U.S. Pat. No. 5,908,906(Kunzler et al.); and U.S. Pat. No. 6,891,010 (Kunzler et al.), thedisclosures of which are incorporated herein by reference. For example,the silicon-containing monomers can be prepared as generally representedin Scheme 1 below:

Although the monomeric mixtures containing the forgoing ethylenicallyterminated silicone-containing monomers can form a crosslinkedthree-dimensional network when polymerized, a wide variety of additionalmonomers may be added to the monomer mixture to provide alternativepolymerization products, e.g., copolymers in random or block sequences,having a wide range of properties depending on the desired drug deliverysystems. Examples of additional monomers and prepolymers includecrosslinking agents such as polyvinyl, typically di- or tri-vinylmonomers, most commonly the di- or tri(meth)acrylates of dihydricethylene glycol, triethylene glycol, butylene glycol, hexane-1,6-diol,thio-diethylene glycol-diacrylate and methacrylate; neopentyl glycoldiacrylate; trimethylolpropane triacrylate and the like;N,N′-dihydroxyethylene-bisacrylamide and -bismethacrylamides; alsodiallyl compounds like diallyl phthalate and triallyl cyanurate;divinylbenzene; ethylene glycol divinyl ether; and the (meth)acrylateesters of polyols such as triethanolamine, glycerol, pentanerythritol,butylene glycol, mannitol, and sorbitol. Further, illustrations includeN,N-methylene-bis-(meth)acrylamide, sulfonated divinylbenzene, anddivinylsulfone. Also useful are the reaction products of hydroxyalkyl(meth)acrylates with unsaturated isocyanates, for example the reactionproduct of 2-hydroxyethyl methacrylate with 2-isocyanatoethylmethacrylate (IEM) as disclosed in U.S. Pat. No. 4,954,587.

Other known crosslinking agents arepolyether-bisurethane-dimethacrylates as described in U.S. Pat. No.4,192,827, and those crosslinkers obtained by reaction of polyethyleneglycol, polypropylene glycol and polytetramethylene glycol with2-isocyanatoethyl methacrylate (IEM) orm-isopropenyl-gamma,gamma,-dimethylbenzyl isocyanates (m-TMI), andpolysiloxane-bisurethane-dimethacrylates as described in U.S. Pat. Nos.4,486,577 and 4,605,712. Still other known crosslinking agents are thereaction products of polyvinyl alcohol, ethoxylated polyvinyl alcohol orof polyvinyl alcohol-co-ethylene with about 0.1 to about 10 mol % vinylisocyanates such as IEM or m-TMI.

Yet other examples include, but are not limited to, hydrophobic andhydrophilic monomers such as methyl methacrylate, 2-ethylhexylmethacrylate, benzyl methacrylate, 2-phenylethyl methacrylate, dimethylitaconate, trifluoromethyl methacrylate, hexafluoroisopropylmethacrylate, bis(hexafluoroisopropyl) methacrylate, 2-hydroxyethylmethacrylate, hydroxyethoxyethyl methacrylate, hydroxydiethoxyethylmethacrylate, methoxyethyl methacrylate, methoxyethoxyethylmethacrylate, methoxydiethoxyethyl methacrylate, poly(ethylene glycol)methacrylate, methoxy-poly(ethylene glycol) methacrylate, methacrylicacid, acrylic acid, itaconic acid, acrylic anhydride, methacrylicanhydride, maleic anhydride, itaconic anhydride, glycerol methacrylate,hydroxypropyl methacrylate, N,N-dimethylacrylamide, acrylamide,N-methylacrylamide, N-vinylpyrrolidione, N-isopropylacrylamide,hydroxybutyl methacrylate and the like and mixtures thereof.

In one embodiment, a monomeric mixture can contain from about 1 to about50 weight percent and preferably from about 5 to about 20 weight percentof monomeric units represented by formula I, from about 10 to about 89weight percent and preferably about 25 to about 50 weight percent ofsilicone-containing monomeric units other than those represented byformula I, and from about 10 to about 70 weight percent and preferablyfrom about 20 to about 60 weight percent of hydrophilic or hydrophobicmonomeric units.

Polymerization of the monomeric mixture can be carried out in any knownmanner. For example, the component(s) in the reaction mixture can beadded continuously to a stirred reactor or can take place in a tubularreactor in which the components can be added at one or more points alongthe tube. In one embodiment, polymerization may be carried out at atemperature of from about 20° C. to about 100° C. and for a timesufficient to polymerize the silicone-containing monomers(s) andoptional monomer(s), e.g., from about 5 minutes to about 16 hours.

In another embodiment, polymerization can be carried out by exposing thereactive monomer(s) to, for example, ultraviolet (UV) or visible lightor electron beams, in the presence of one or more photoinitiator(s). Theuse of UV or visible light in combination with photoinitiators is wellknown in the art and is particularly suitable for formation of thepolymerization product. Suitable photoinitiators which are useful forpolymerizing the polymerizable mixture of monomers can be commerciallyavailable photoinitiators, e.g., photoinitiators commercially availableunder the “IRGACURE”, “DAROCUR” and “SPEEDCURE” trade names(manufactures by Ciba Specialty Chemicals, also obtainable under adifferent name from BASF, Fratelli Lamberti and Kawaguchi). They aregenerally compounds which are capable of initiating the radical reactionof olefinically unsaturated double bonds on exposure to light with awavelength of, for example, about 260 to about 480 mn.

Generally, pharmaceutically active agents or drugs useful in the matrixcontrolled diffusion drug delivery systems of the present invention canbe any compound, composition of matter, or mixtures thereof that can bedelivered from the drug delivery system to produce a beneficial anduseful result to, for example, the eye, especially an agent effective inobtaining a desired local or systemic physiological or pharmacologicaleffect. Examples of such agents include, but are not limited to,anesthetics and pain killing agents such as lidocaine and relatedcompounds, benzodiazepam and related compounds and the like; anti-canceragents such as 5-fluorouracil, adriamycin and related compounds and thelike; anti-fungal agents such as fluconazole and related compounds andthe like; anti-viral agents such as trisodium phosphomonoformate,trifluorothymidine, acyclovir, ganciclovir, DDI, AZT and the like; celltransport/mobility impending agents such as colchicine, vincristine,cytochalasin B and related compounds and the like; antiglaucoma drugssuch as beta-blockers, e.g., timolol, betaxolol, atenalol, and the like;antihypertensives; decongestants such as phenylephrine, naphazoline,tetrahydrazoline and the like; immunological response modifiers such asmuramyl dipeptide and related compounds and the like; peptides andproteins such as cyclosporin, insulin, growth hormones, insulin relatedgrowth factor, heat shock proteins and related compounds and the like;steroidal compounds such as dexamethasone, prednisolone and relatedcompounds and the like; low solubility steroids such as fluocinoloneacetonide and related compounds and the like; carbonic anhydraseinhibitors; diagnostic agents; antiapoptosis agents; gene therapyagents; sequestering agents; reductants such as glutathione and thelike; antipermeability agents; antisense compounds; antiproliferativeagents; antibody conjugates; antidepressants; bloodflow enhancers;antiasthmatic drugs; antiparasiticagents; non-steroidal antiinflammatory agents such as ibuprofen and the like; nutrients andvitamins: enzyme inhibitors: antioxidants; anticataract drugs; aldosereductase inhibitors; cytoprotectants; cytokines, cytokine inhibitors,and cytokin protectants; uv blockers; mast cell stabilizers; antineovascular agents such as antiangiogenic agents, e.g., matrixmetalloprotease inhibitors and the like.

Representative examples of additional pharmaceutically active agent foruse herein include, but are not limited to, neuroprotectants such asnimodipine and related compounds and the like; antibiotics such astetracycline, chlortetracycline, bacitracin, neomycin, polymyxin,gramicidin, oxytetracycline, chloramphenicol, gentamycin, erythromycinand the like; anti-infectives; antibacterials such as sulfonamides,sulfacetamide, sulfamethizole, sulfisoxazole; nitrofurazone, sodiumpropionate and the like; antiallergenics such as antazoline,methapyriline, chlorpheniramine, pyrilamine, prophenpyridamine and thelike; anti-inflammatories such as hydrocortisone, hydrocortisoneacetate, dexamethasone 21 -phosphate, fluocinolone, medrysone,methylprednisolone, prednisolone 21-phosphate, prednisolone acetate,fluoromethalone, betamethasone, triminolone and the like; miotics;anti-cholinesterase such as pilocarpine, eserine salicylate, carbachol,di-isopropyl fluorophosphate, phospholine iodine, demecarium bromide andthe like; miotic agents; mydriatics such as atropine sulfate,cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine,hydroxyamphetamine and the like; svmpathomimetics such as epinephrineand the like; and prodrugs such as, for example, those described inDesign of Prodrugs, edited by Hans Bundgaard, Elsevier ScientificPublishing Co., Amsterdam, 1985. In addition to the foregoing agents,other agents suitable for treating, managing, or diagnosing conditionsin a mammalian organism may be entrapped in the copolymer andadministered using the drug delivery systems of the current invention.Once again, reference may be made to any standard pharmaceuticaltextbook such as, for example, Remington's Pharmaceutical Sciences forpharmaceutically active agents.

Any pharmaceutically acceptable form of the foregoing pharmaceuticallyactive agent may be employed in the practice of the present invention,e.g., the free base; free acid; pharmaceutically acceptable salts,esters or amides thereof, e.g., acid additions salts such as thehydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate,valerate, oleate, palmitate, stearate, laurate, borate, benzoate,lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate,succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and laurylsulfate salts and the like; alkali or alkaline earth metal salts such asthe sodium, calcium, potassium and magnesium salts and the like;hydrates; enantiomers; isomers; stereoisomers; diastereoisomers;tautomers; polymorphs, mixtures thereof, prodrugs thereof or racematesor racemic mixtures thereof.

Actual dosage levels of the pharmaceutically active agent(s) in the drugdelivery systems of the present invention may be varied to obtain anamount of the pharmaceutically active agent(s) that is effective toobtain a desired therapeutic response for a particular system and methodof administration. The selected dosage level therefore depends upon suchfactors as, for example, the desired therapeutic effect, the route ofadministration, the desired duration of treatment, and other factors.The total daily dose of the pharmaceutically active agent(s)administered to a host in single or divided doses can vary widelydepending upon a variety of factors including, for example, the bodyweight, general health, sex, diet, time and route of administration,rates of absorption and excretion, combination with other drugs, theseverity of the particular condition being treated, etc. Generally, theamounts of pharmaceutically active agent(s) present in the drug deliverysystems of the present invention can range from about 0.1% w/w to about60% w/w and preferably from about 1% w/w to about 50% w/w.

Polymerization products of the monomeric mixtures containing at leastone or more of the silicon-containing monomers may be combined with oneor more pharmaceutically active agents to form the drug delivery systemsof the present invention. By controlling the concentration of thehydrophobic and hydrophilic groups on the siloxane backbone, hydrophobicand hydrogen-bonding interactions with the drug can occur. For example,if fluoroalkyl pendant groups on the siloxane polymer are present,greater solubility of a fluorinated drug in the polymer matrix will berealized, thus giving longer sustained delivery of the drug. If thisenhanced solubility of drug is incorporated with added hydrophilichydrogen bonding, the sustained release characteristics of the drug willbe further enhanced. Additionally, if the siloxane polymer containshydrophilic anionic sites, such as from carboxylic acid groups, theseanionic groups can ionically interact with cationic drugs, thus slowingand extending the release of drug. The hydrophobic/hydrophilic balanceof characteristics may thus be manipulated to achieve the desired rateof drug release. The desired rate of drug release may be determinedbased on the drug to be delivered, the location of delivery, the purposeof delivery and/or the therapeutic requirements of the individualpatient. The hydrophobic/hydrophilic balance of characteristics dictatesthe solubility of the drug, and is a primary factor controlling the rateof drug release.

Generally, the drug delivery systems of the present invention can beprepared by first forming the polymerization product of a monomericmixture as described hereinabove and then entrapping a therapeuticallyeffective amount of one or more of pharmaceutically active agentstherein. In one embodiment, the process may include at least (a) forminga polymerization product of a monomeric mixture as describedhereinabove; (b) swelling the polymerization product in a swellingsolution comprising one or more solvents and a therapeutically effectiveamount of at least one pharmaceutically active agent; and (c) removingthe polymerization product from the solution to provide the matrixcontrolled diffusion drug delivery system comprising the therapeuticallyeffective amount of one or more pharmaceutically active agents entrappedin the polymerization product.

In step (b) of the process, the polymerization product can be swelledwith the swelling solution by, for example, immersing the polymerizationproduct in the swelling solution for a time period sufficient to entrapthe pharmaceutically active agent in the polymerization product, e.g., atime period of from about 1 hour to about 24 hours. The swellingsolution will ordinarily include at least one or more solvents and atherapeutically effective amount of the one or more pharmaceuticallyactive agents. Suitable solvents include, but are not limited to,ketones, alcohols, ethers, aliphatic hydrocarbons, aromatichydrocarbons, sulfoxides, amide-based solvents and the like and mixturesthereof.

Suitable ketones for use herein can be one or more ketones of thegeneral formula R²⁶R²⁷C(O) wherein R²⁶ and R²⁷ are the same or differentand can be a substituted or unsubstituted C₁-C₃₀ alkyl, a substituted orunsubstituted C₃-C₃₀ cycloalkyl, a substituted or unsubstituted C₃-C₃₀cycloalkylalkyl, a substituted or unsubstituted C₃-C₃₀ cycloalkenyl, asubstituted or unsubstituted C₅-C₃₀ aryl, a substituted or unsubstituteda C₅-C₃₀ arylalkyl, a substituted or unsubstituted C₅-C₃₀ heteroaryl, asubstituted or unsubstituted C₃-C₃₀ heterocyclic ring, a substituted orunsubstituted C₄-C₃₀ heterocyclylalkyl, a substituted or unsubstitutedC₆-C₃₀ heteroarylalkyl; or R²⁶ and R²⁷ together with the carbon atom towhich they are bonded are joined together to form a saturated orunsaturated ring optionally containing one or more heterocyclic atoms.In another embodiment, the ketones for use herein include thosecontaining at least three carbon atoms. Representative examples ofketones for use herein include, but are not limited to, acetone, methylethyl ketone, diethyl ketone, methyl propyl ketone, methyl isopropylketone, ethyl propyl ketone, ethyl isopropyl ketone, dipropyl ketone,diisopropyl ketone, methyl butyl ketone, methyl isobutyl ketone, methylsec butyl ketone, methyl tert-butyl ketone, ethyl butyl ketone, ethylisobutyl ketone, ethyl sec-butyl ketone, ethyl tert-butyl ketone, propylbutyl ketone, isopropyl butyl ketone, propyl isobutyl ketone, propylsec-butyl ketone, propyl tert butyl ketone, isopropyl isobutyl ketone,isopropyl sec-butyl ketone, isopropyl tert-butyl ketone, dibutyl ketone,diisobutyl ketone, di-sec-butyl ketone, di-tert-butyl ketone, butylisobutyl ketone, butyl sec-butyl ketone, butyl tert-butyl ketone,isobutyl sec-butyl ketone, isobutyl tert-butyl ketone, sec-butyltert-butyl ketone, 5-heptanone, 5-methyl-2-hexanone (methyl isoamylketone), 4-methyl-2-hexanone, 3-methyl-2-hexanone,3,4-dimethyl-2-pentanone, 3,3-dimethyl-2-pentanone,4,4-dimethyl-2-pentanone, 3-octanone, 4-methyl-3-heptanone,5-methyl-3-heptanone, 6-methyl-3-heptanone, 4,4-dimethyl-3-hexanone,4,5-dimethyl-3-hexanone, 5,5-dimethyl-3-hexanone, 4-nonanone,5-methyl-4-octanone, 6-methyl-4-octanone, 7-methyl-4-octanone,5,5-dimethyl-4 5,6-dimethyl-4-heptanone, 6,6-dimethyl-4-heptanone,2-undecanone, cyclopropanone, cyclobutanone, cyclopentanone,cyclohexanone, cycloheptanone, cyclooctanone, cyclononanone,cyclodecanone, cycloundecanone, cyclododecanone and the like andcombinations thereof. A preferred ketone for use herein is acetone.

Suitable alcohols for use herein include, but are not limited to, C₁-C₃₀aliphatic alcohols, C₆-C₃₀ aromatic alcohols and the like and mixturesthereof. Examples of useful alcohols include, but are not limited to,methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butylalcohol, benzyl alcohol and the like and mixtures thereof. A preferredalcohol for use herein is isopropyl alcohol.

Suitable ether solvents for use herein include, but are not limited to,tetrahydrofuran and the like and mixtures thereof. Suitable aliphatichydrocarbon solvents for use herein include, but are not limited to,hexane, heptane, and the like and mixtures thereof. Suitable aromatichydrocarbon solvents for use herein include, but are not limited to,toluene, benzene, xylene and the like and mixtures thereof. Suitablesulfoxide solvents for use herein include, but are not limited to,dimethylsulfoxide (DMSO), sulfolane and the like and mixtures thereof.Suitable amide-based solvents for use herein include, but are notlimited to, pyrrolidine, dimethylformamide (DMF), dimethylacetamide(DMA) and the like and mixtures thereof.

Generally, the amount of solvent employed in the solution will rangefrom about 5% w/w to about 500% w/w and preferably from about 10% w/w toabout 200% w/w.

Next, the polymerization product will be taken out of the solution andthe solvent will be substantially removed from the swelledpolymerization product to provide the drug delivery system of thepresent invention. The solvent can be substantially removed from theswelled polymerization product by techniques known in the art such as,for example, drying, e.g., air drying, vacuum drying, freeze drying,drying under an inert gas (e.g., nitrogen), in an oven at elevatedtemperatures and the like.

In an alternate embodiment, the drug delivery systems of the presentinvention can be prepared by polymerizing the monomeric mixture underpolymerization conditions as discussed above in the presence of one ormore pharmaceutically active agents such that the pharmaceuticallyactive agent(s) is entrapped in the polymerization product. As oneskilled in the art will readily appreciate, the resulting polymerizationproduct may have some pharmaceutically active agent(s) which iscovalently bound to the polymerization product as well as some freestarting monomer(s). If desired, these reactants may be removed from theresulting product by conventional techniques.

The matrix controlled diffusion drug delivery systems of the presentinvention may be manufactured in any suitable form, shape, e.g.,circular, rectangular, tubular, square and triangular shapes, or sizesuitable for the treatment which they are intended to be used. Methodsof forming the subject matrix controlled diffusion drug delivery systemsinclude, but are not limited to, cast molding, injection/compressionmolding, extrusion, and other methods known to those skilled in the art.The drug delivery systems of the present invention are advantageouslysized and configured for back of the eye delivery, e.g., for use as aninner back of the eye implant such as a hollow cylinder or tube having afirst cross dimension (diameter and width), ranging from about 1 mm toabout 5 mm and a second cross dimension, such as length, from about 0.2mm to about 10 mm.

Alternatively, the drug delivery system can be in the form of asolution, suspension, solution/suspension, microsphere or nanosphereusing a pharmaceutically acceptable carrier well known in the art.Additionally, the solution, suspension, solution/suspension, microsphereor nanosphere can contain one or more pharmaceutically acceptableexcipients such as suspending agents, e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodiumalginate, poly(N-vinylpyrrolidone), gum tragacanth and gum acacia;dispersing or wetting agents, e.g., naturally occurring phosphatide,e.g., lecithin, or condensation products of an alkylene oxide with fattyacids, e.g., polyoxyethylene stearate, or condensation products ofethylene oxide with long chain aliphatic alcohols, e.g.,heptadecaethylene-oxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol, e.g.,polyoxyethylene sorbitol monoleate or condensation products of ethyleneoxide with partial esters derived from fatty acids and hexitolanhydrides, e.g., polyoxyethylene sorbitan monoleate. Once manufactured,the subject matrix controlled diffusion drug delivery systems arepackaged and sterilized using customary methods known to those skilledin the art.

Matrix controlled diffusion drug delivery systems of the presentinvention may be used in a broad range of therapeutic applications. Thematrix controlled diffusion drug delivery systems of the presentinvention are particularly useful in the treatment of ophthalmicdiseases, disorders and/or injuries. Representative examples of suchophthalmic diseases, disorders or injuries include, but are not limitedto, diabetic retinopathy, glaucoma, macular degeneration, retinitispigmentosa, retinal tears or holes, retinal-detachment, retinalischemia, acute retinopathies associated with trauma, inflammatorymediated degeneration, post-surgical complications, damage associatedwith laser therapy including photodynamic therapy (PDT), surgical lightinduced iatrogenic retinopathy, drug-induced retinopathies, autosomaldominant optic atrophy, toxic/nutritional amblyopias; leber's hereditaryoptic neuropathy (LHOP), other mitochondrial diseases with ophthalmicmanifestations or complications, angiogenesis; atypical RP; bardet-biedlsyndrome; blue-cone monochromacy; cataracts; central areolar choroidaldystrophy; choroideremia; cone dystrophy; rod dystrophy; cone-roddystrophy; rod-cone dystrophy; congenital stationary night blindness;cytomegalovirus retinitis; diabetic macular edema; dominant drusen;giant cell arteritis (GCA); goldmann-favre dystrophy; graves'ophthalmopathy; gyrate atrophy; hydroxychloroquine; iritis; juvenileretinoschisis; kearns-sayre syndrome; lawrence-moon bardet-biedlsyndrome; leber congenital amaurosis; lupus-induced cotton wool spots;macular degeneration, dry form; macular degeneration, wet form; maculardrusen; macular dystrophy; malattia leventinese; ocular histoplasmosissyndrome; oguchi disease; oxidative damage; proliferativevitreoretinopathy; refsum disease; retinitis punctata albescens;retinopathy of prematurity; rod monochromatism; RP and usher syndrome;scleritis; sector RP; sjogren-larsson syndrome; sorsby fundus dystrophy;stargardt disease and other retinal diseases.

The drug delivery systems of the present invention can be administeredto a mammal in need of treatment by way of a variety of routes. Forexample, the drug delivery systems may be used by implantation within aportion of the body in need of localized drug delivery, e.g., theinterior portion of an eye. However, the subject matrix controlleddiffusion drug delivery systems may likewise be used in accordance withother surgical procedures known to those skilled in the field ofophthalmology. For example, the drug delivery systems can beadministered to the region of the eye in need of treatment employinginstruments known in the art, e.g., a flexible microcatheter system orcannula disclosed in U.S. Patent Application Publication No.2002/0002362, or the intraretinal delivery and withdrawal systemsdisclosed in U.S. Pat. Nos. 5,273,530 and 5,409,457, the contents ofeach which are incorporated by reference herein. The pharmaceuticallyactive agent may be released from the drug delivery device over asustained and extended period of time. Optionally, the drug release ratemay also be controlled through the attachment of an inert diffusionbarrier by way of, for example, surface treatment of the drug deliverydevice. The surface treatment may be applied through a variety ofsurface treatment techniques known in the art, e.g., oxidative plasma,evaporative deposition, dip coating or extrusion techniques.

The following examples are provided to enable one skilled in the art topractice the invention and are merely illustrative of the invention. Theexamples should not be read as limiting the scope of the invention asdefined in the claims.

EXAMPLE 1 Synthesis of 1,3-bis(4-methacryloyloxybutyl)tetramethyldisiloxane (M₂)

To a four neck resin flask equipped with a mechanical stirrer,Dean-Stark trap, heating mantle, water cooled condenser and thermometerwas added 1,1-dimethyl-1-sila-2-oxacyclohexane, methacrylic acid, andconcentrated sulfuric acid. To the reaction mixture was then addedcyclohexane and hydroquinone as a polymerization inhibitor. The reactionmixture was heated to reflux for five hours during which time of waterwas collected. The reaction mixture was then cooled, divided, and passedthrough two chromatography columns filled with alumina (packed usingcyclohexane as eluant). The cyclohexane was removed using a rotaryevaporator and the resultant M₂ is placed under vacuum for one hour at80° C.

EXAMPLE 2 Synthesis of a methacrylate-terminated siloxane (M₂D₂)

To a round bottom flask under dry nitrogen was added D₄(octamethylcyclotetrasiloxane) and the M₂ prepared in Example 1.Trifluoromethane sulfonic acid was added as initiator. The reactionmixture was stirred 24 hours with vigorous stirring at room temperature.Sodium bicarbonate is then added and the reaction mixture was againstirred for 24 hours. The resultant solution was filtered through a 0.3μTeflon® filter. The filtered solution was vacuum stripped and placedunder vacuum (>0.1 mm Hg) at 50° C. to remove the unreacted siliconecyclics. The resulting methacrylate terminated siloxane was a viscous,clear fluid.

EXAMPLE 3

To 100 parts of the methacrylate terminated siloxane prepared in Example2 (where x=2) was added 1.0% Irgacure 819 as a photoinitiator and 20%w/w of fluocinolone acetonide (FA). The suspension was added to Teflontubes (0.5 mm in diameter) available from Boramed (Durham, N.C.) andpolymerized using visible light polymerization techniques. The cureconditions consisted of two hours of visible light irradiation.Following the cure the drug loaded copolymer was removed from tuberesulting in a release device having dimensions of 5 mm by 0.5 mm.

EXAMPLE 4 Drug Release

The sample as prepared in Example 3 was placed in 3 cc of borate bufferin a sealed glass tube and the amount of FA release is monitored at 34°C. At periodic intervals, 3 cc of solution is removed and replaced with3 cc of fresh borate. The solution is analyzed by liquid chromatography(LC) for FA. The release rate per day and percent cumulative releasewere determined. A zero-order drug release is obtained shortly after theinitial burst as shown in FIG. 1 for M₂D₂ (200A).

EXAMPLE 5 Synthesis of a methacrylate-terminated siloxane (M₂D₅₀)

To a round bottom flask under dry nitrogen was added D₅₀ and the M₂prepared in Example 1. Trifluoromethane sulfonic acid was added asinitiator. The reaction mixture was stirred 24 hours with vigorousstirring at room temperature. Sodium bicarbonate is then added and thereaction mixture was again stirred for 24 hours. The resultant solutionwas filtered through a 0.3μ Teflon® filter. The filtered solution wasvacuum stripped and placed under vacuum (>0.1 mm Hg) at 50° C. to removethe unreacted silicone cyclics. The resulting methacrylate terminatedsiloxane was a viscous, clear fluid.

EXAMPLE 6

To 100 parts of the methacrylate terminated siloxane prepared in Example5 was added 1.0% Irgacure 819 as a photoinitiator and 20% w/w of FA. Thesuspension was added to Teflon tubes (0.5 mm in diameter) available fromBoramed (Durham, N.C.) and polymerized using visible lightpolymerization techniques. The cure conditions consisted of two hours ofvisible light irradiation. Following the cure the drug loaded copolymerwas removed from tube resulting in a release device having dimensions of5 mm by 0.5 mm.

EXAMPLE 7 Drug Release

The sample as prepared in Example 6 was placed in 3 cc of borate bufferin a sealed glass tube and the amount of FA release was monitored at 34°C. At periodic intervals, 3 cc of solution is removed and replaced with3 cc of fresh borate. The solution was analyzed by LC for FA. Therelease rate per day and percent cumulative release were determined. Azero-order drug release was obtained shortly after the initial burst asshown in FIG. 2 for M₂D₅₀ (195A).

It will be understood that various modifications may be made to theembodiments disclosed herein. Therefore the above description should notbe construed as limiting, but merely as exemplifications of preferredembodiments. For example, the functions described above and implementedas the best mode for operating the present invention are forillustration purposes only. Other arrangements and methods may beimplemented by those skilled in the art without departing from the scopeand spirit of this invention. Moreover, those skilled in the art willenvision other modifications within the scope and spirit of the featuresand advantages appended hereto.

1. A matrix controlled diffusion drug delivery system comprising atherapeutically effective amount of one or more pharmaceutically activeagents entrapped in a polymerization product of a monomeric mixturecomprising one or more silicone-containing monomers of the generalformula:

wherein x and y are independently integers from 0 to about 300; m and m′are independently integers from 1 to about 6, R is independently astraight or branched, substituted or unsubstituted, C₁-C₃₀ alkyl group,a C₁-C₃₀ fluoroalkyl group, an ether or polyether containing group or aC₁-C₃₀ alkylamide group, R₁, R², R³, R⁴, R⁵, R⁶ and R⁷ are independentlyhydrogen, a straight or branched C₁-C₃₀ alkyl group, a C₁-C₃₀fluoroalkyl group, a C₁-C₂₀ ester group, an alkyl ether, cycloalkylether, cycloalkylalkyl ether, cycloalkenyl ether, aryl ether, arylalkylether or polyether containing group, an ureido group, an amide group, anamine group, a substituted or unsubstituted C₁-C₃₀ alkoxy group, asubstituted or unsubstituted C₃-C₃₀ cycloalkyl group, a substituted orunsubstituted C₃-C₃₀ cycloalkylalkyl group, a substituted orunsubstituted C₃-C₃₀ cycloalkenyl group, a substituted or unsubstitutedC₅-C₃₀ aryl group, a substituted or unsubstituted C₅-C₃₀ arylalkylgroup, a substituted or unsubstituted C₅-C₃₀ heteroaryl group, asubstituted or unsubstituted C₃-C₃₀ heterocyclic ring, a substituted orunsubstituted C₄-C₃₀ heterocyclolalkyl group, a substituted orunsubstituted C₆-C₃₀ heteroarylalkyl group, fluorine, a vinyl group, aC₅-C₃₀ fluoroaryl group, or a hydroxyl group; X is independently astraight or branched C₁-C₃₀ alkyl group, a C₁-C₃₀ fluoroalkyl group, asubstituted or unsubstituted C₅-C₃₀ arylalkyl group, a substituted orunsubstituted C₁-C₃₀ alkoxy group, an ether, polyether, sulfide, oramino containing group and Z and Z′ are independently a polymerizableethylenically unsaturated organic radical, wherein the matrix controlleddiffusion drug delivery system is sized and configured for back of theeye delivery.
 2. The matrix controlled diffusion drug delivery system ofclaim 1, wherein x is 2 to about 100, y is 2 to about 100, R¹, R², R³,R⁴, R⁵, R⁶ and R⁷ are independently a branched C¹-C₃₀ alkyl group, and Zand Z′ are selected from an ester or amide of acrylic or methacrylicacid.
 3. The matrix controlled diffusion drug delivery system of claim1, wherein x is 2 to about 100, y is 2 to about 100, R¹, R², R³, R⁴, R⁵,R⁶ and R⁷ are independently a straight or branched C₁-C₆ alkyl group Xis a bond or an ether or polyether containing group, and Z and Z′ areindepenedently an ester or amide of acrylic or methacrylic acid.
 4. Thematrix controlled diffusion drug delivery system of claim 1, wherein xis 2 to about 100, y is 2 to about 100, R is independently a straight orbranched C₁-C₃₀ fluoroalkyl group, an alkyl ether or polyether group ora straight or branched C ₁-C₃₀ alkylamide group, R¹, R², R³, R⁴, R⁵, R⁶and R⁷ are independently a straight or branched C₁-C₆ alkyl group, X isindependently a bond or one or more C₁-C₃₀ alkyl ether groups orpolyether groups and Z and Z′ are independently an ester or amide ofacrylic or methacrylic acid.
 5. The matrix controlled diffusion drugdelivery system of claim 1, wherein the one or more pharmaceuticallyactive agents is selected from the group consisting of an anti-glaucomaagent, anti-cataract agent, anti-diabetic retinopathy agent, thiolcross-linking agent, anti-cancer agent, immune modulator agent,anti-clotting agent, anti-tissue damage agent, anti-inflammatory agent,anti-fibrous agent, non-steroidal anti-inflammatory agent, antibiotic,anti-pathogen agent, piperazine derivative, cycloplegic agent, mioticagent, mydriatic agent and mixtures thereof.
 6. The matrix controlleddiffusion drug delivery system of claim 1, wherein the one or morepharmaceutically active agents is selected from the group consisting ofan anticholinergic, anticoagulant, antifibrinolytic, antihistamine,antimalarial, antitoxin, chelating agent, hormone, immunosuppressive,thrombolytic, vitamin, protein, salt, desensitizer, prostaglandin, aminoacid, metabolite, antiallergenic and mixtures thereof.
 7. The matrixcontrolled diffusion drug delivery system of claim 1, wherein themonomeric mixture comprises one or more other monomers or prepolymers.8. The matrix controlled diffusion drug delivery system of claim 5,wherein the one or more monomers are selected from the group consistingof methyl methacrylate, 2-ethylhexyl methacrylate, benzyl methacrylate,2-phenylethyl methacrylate, dimethyl itaconate, trifluoromethylmethacrylate, hexafluoroisopropyl methacrylate, bis(hexafluoroisopropyl)methacrylate, 2-hydroxyethyl methacrylate, hydroxyethoxyethylmethacrylate, hydroxydiethoxyethyl methacrylate, methoxyethylmethacrylate, methoxyethoxyethyl methacrylate, methoxydiethoxyethylmethacrylate, poly(ethylene glycol) methacrylate, methoxy-poly(ethyleneglycol) methacrylate, methacrylic acid, acrylic acid, itaconic acid,acrylic anhydride, methacrylic anhydride, maleic anhydride, itaconicanhydride, glycerol methacrylate, hydroxypropyl methacrylate,N,N-dimethylacrylamide, acrylamide, N-methylacrylamide,N-vinylpyrrolidione, N-isopropylacrylamide, hydroxybutyl methacrylateand mixtures thereof.
 9. The matrix controlled diffusion drug deliverysystem of claim 1, in a form of a solution, suspension,solution/suspension, microsphere or nanosphere.
 10. The matrixcontrolled diffusion drug delivery system of claim 1, in a form of asemi-solid or solid article suitable for ocular implant.
 11. A processfor preparing a matrix controlled diffusion drug delivery system sizedand configured for back of the eye delivery, the process comprisingentrapping a therapeutically effective amount of one or morepharmaceutically active agents in a polymerization product of amonomeric mixture comprising one or more silicone-containing monomers ofthe general formula:

wherein x and y are independently integers from 0 to about 300; m and m′are independently integers from 1 to about 6, R is independently astraight or branched, substituted or unsubstituted, C₁-C₃₀ alkyl group,a C₁-C₃₀ fluoroalkyl group, an ether or polyether containing group or aC₁-C₃₀ alkylamide group, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independentlyhydrogen, a straight or branched C₁-C₃₀ alkyl group, a C₁-C₃₀fluoroalkyl group, a C₁-C₂₀ ester group, an alkyl ether, cycloalkylether, cycloalkylalkyl ether, cycloalkenyl ether, aryl ether, arylalkylether or polyether containing group, an ureido group, an amide group, anamine group, a substituted or unsubstituted C₁-C₃₀ alkoxy group, asubstituted or unsubstituted C₃-C₃₀ cycloalkyl group, a substituted orunsubstituted C₃-C₃₀ cycloalkylalkyl group, a substituted orunsubstituted C₃-C₃₀ cycloalkenyl group, a substituted or unsubstitutedC₅-C₃₀ aryl group, a substituted or unsubstituted C₅-C₃₀ arylalkylgroup, a substituted or unsubstituted C₅-C₃₀ heteroaryl group, asubstituted or unsubstituted C₃-C₃₀ heterocyclic ring, a substituted orunsubstituted C₄-C₃₀ heterocyclolalkyl group, a substituted orunsubstituted C₆-C₃₀ heteroarylalkyl group, fluorine, a vinyl group, aC₅-C₃₀ fluoroaryl group, or a hydroxyl group; X is independently astraight or branched C₁-C₃₀ alkyl group, a C₁-C₃₀ fluoroalkyl group, asubstituted or unsubstituted C₅-C₃₀ arylalkyl group, a substituted orunsubstituted C₁-C₃₀ alkoxy group, an ether, polyether, sulfide, oramino containing group and Z and Z′ are independently a polymerizableethylenically unsaturated organic radical.
 12. The process of claim 11,wherein the step of entrapping the therapeutically effective amount ofone or more pharmaceutically active agents in the polymerization productcomprises polymerizing the monomeric mixture in the presence of the thetherapeutically effective amount of one or more pharmaceutically activeagents.
 13. A process for preparing a matrix controlled diffusion drugdelivery system, the process comprising (a) swelling a polymerizationproduct of a monomeric mixture comprising one or moresilicone-containing monomers of the general formula:

wherein x and y are independently integers from 0 to about 300; m and m′are independently integers from 1 to about 6, R is independently astraight or branched, substituted or unsubstituted, C₁-C₃₀ alkyl group,a C₁-C₃₀ fluoroalkyl group, an ether or polyether containing group or aC₁-C₃₀ alkylamide group, R₁, R², R³, R⁴, R⁵, R⁶ and R⁷ are independentlyhydrogen, a straight or branched C₁-C₃₀ alkyl group, a C₁-C₃₀fluoroalkyl group, a C₁-C₂₀ ester group, an alkyl ether, cycloalkylether, cycloalkylalkyl ether, cycloalkenyl ether, aryl ether, arylalkylether or polyether containing group, an ureido group, an amide group, anamine group, a substituted or unsubstituted C₁-C₃₀ alkoxy group, asubstituted or unsubstituted C₃-C₃₀ cycloalkyl group, a substituted orunsubstituted C₃-C₃₀ cycloalkylalkyl group, a substituted orunsubstituted C₃-C₃₀ cycloalkenyl group, a substituted or unsubstitutedC₅-C₃₀ aryl group, a substituted or unsubstituted C₅-C₃₀ arylalkylgroup, a substituted or unsubstituted C₅-C₃₀ heteroaryl group, asubstituted or unsubstituted C₃-C₃₀ heterocyclic ring, a substituted orunsubstituted C₄-C₃₀ heterocyclolalkyl group, a substituted orunsubstituted C₆-C₃₀ heteroarylalkyl group, fluorine, a vinyl group, aC₅-C₃₀ fluoroaryl group, or a hydroxyl group; X is independently astraight or branched C₁-C₃₀ alkyl group, a C₁-C₃₀ fluoroalkyl group, asubstituted or unsubstituted C₅-C₃₀ arylalkyl group, an ether,polyether, sulfide, or amino containing group and Z and Z′ areindependently a polymerizable ethylenically unsaturated organic radical,in a swelling solution comprising one or more solvents and atherapeutically effective amount of one or more pharmaceutically activeagents; and (b) removing the polymerization product from the solution toprovide the matrix controlled diffusion drug delivery system comprisingthe therapeutically effective amount of one or more pharmaceuticallyactive agents entrapped in the polymerization product.
 14. The processof claim 13, wherein x is 2 to about 100, y is 2 to about 100, R¹, R²,R³, R⁴, R⁵, R⁶ and R⁷ are independently a straight or branched C₁-C₃₀alkyl group, and Z and Z′ are selected from an ester or amide of acrylicor methacrylic acid.
 15. The process of claim 13, wherein x is 2 toabout 100, y is 2 to about 100, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ areindependently a straight or branched C₁-C₆ alkyl group X is a bond or anether or polyether containing group, and Z and Z′ are indepenedently anester or amide of acrylic or methacrylic acid.
 16. The process of claim13, wherein x is 2 to about 100, y is 2 to about 100, R is independentlya straight or branched C₁-C₃₀ fluoroalkyl group, an alkyl ether orpolyether group or a straight or branched C₁-C₃₀ alkylamide group, R¹,R², R³, R⁴, R⁵, R⁶ and R₇ are independently a straight or branched C₁-C₆alkyl group, X is independently a bond or one or more C₁-C₃₀ alkyl ethergroups or polyether groups and Z and Z′ are independently an ester oramide of acrylic or methacrylic acid.
 17. The process of claim 13,wherein the one or more pharmaceutically active agents is selected fromthe group consisting of an anti-glaucoma agent, anti-cataract agent,anti-diabetic retinopathy agent, thiol cross-linking agent, anti-canceragent, immune modulator agent, anti-clotting agent, anti-tissue damageagent, anti-inflammatory agent, anti-fibrous agent, non-steroidalanti-inflammatory agent, antibiotic, anti-pathogen agent, piperazinederivative, cycloplegic agent, miotic agent, mydriatic agent andmixtures thereof.
 18. The process of claim 13, wherein the one or morepharmaceutically active agents is selected from the group consisting ofan anticholinergic, anticoagulant, antifibrinolytic, antihistamine,antimalarial, antitoxin, chelating agent, hormone, immunosuppressive,thrombolytic, vitamin, protein, salt, desensitizer, prostaglandin, aminoacid, metabolite, antiallergenic and mixtures thereof.
 19. The processof claim 13, wherein the monomeric mixture comprises one or more othermonomers or prepolymers.
 20. The process of claim 13, wherein thesolvent in the solution is selected from the group consisting of aketone, alcohol, ether, aliphatic hydrocarbon, aromatic hydrocarbon,sulfoxide, amide-based solvent and mixtures thereof.
 21. The process ofclaim 13, wherein in the step of removing the polymerization productfrom the solution comprises removing the polymerization product from thesolution and drying the polymerization product.
 22. A method fortreating a mammal, the method comprising administering to the mammal inneed of such treatment the matrix controlled diffusion drug deliverysystem of claim
 1. 23. The method of claim 22, wherein the step ofadministering comprises: creating an incision within an eye; andimplanting the matrix controlled diffusion drug delivery system withinthe eye through the incision.
 24. The method of claim 22, wherein thestep of administering comprises: injecting the matrix controlleddiffusion drug delivery system within an eye.
 25. A method of treatingan ophthalmic state, disease, disorder, injury or condition comprisingadministering to a mammal in need of such treatment a matrix controlleddiffusion drug delivery system the drug delivery system of claim
 1. 26.A method of treating an ophthalmic state, disease, disorder, injury orcondition comprising administering to a mammal in need of such treatmenta matrix controlled diffusion drug delivery system the drug deliverysystem of claim 4.